Method of improving flavor of a composition of (d)-beta-hydroxybutyric acid and (d)-1,3 butanediol and use as a nutritional supplement and therapeutic agent

ABSTRACT

A method of improving flavor of a combination of a composition for increasing circulating ketone levels is disclosed. A composition containing (D)-β-hydroxybutyric acid (D-BHB), (D)-β-hydroxyvaleric acid (D-BHV), and (D)-1,3 butanediol (D-1,3BD) is disclosed. Exemplary compositions may be incorporated into food, supplement, and beverage products.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Divisional of U.S. Ser. No. 17/192,220 filed Mar.4, 2021, which claims the benefit of U.S. Provisional Application No.62/985,388 filed on Mar. 5, 2020, and U.S. Provisional Application No.63/079,671 filed on Sep. 17, 2020, the disclosures of which are herebyincorporated by reference in their entireties.

FIELD

This disclosure relates to a new and nonobvious method of improving theflavor of a composition including (D)-β-hydroxybutyric acid, and (D)-1,3butanediol. The disclosure also relates to a methods for improving theperformance of ketone bodies in a food or beverage product by combiningat least (D)-β-hydroxybutyric acid and (D)-1,3 butanediol.

BACKGROUND

During periods of carbohydrate deprivation, the body utilizes energyobtained from the metabolism of fats. During fat metabolism, fats areconverted to ketone bodies. Large quantities of these substancesaccumulate in the blood. This condition, which is known as ketosis, isknown to occur during starvation. When blood ketone body concentrationsare elevated to levels found in prolonged starvation, they provide asignificant source of energy for the brain and body. Studies of certainstates of ketosis have led to the recognition that those states candeliver health benefits. For example, certain states of ketosis areunderstood to play a positive role in aging pathways and in treatment ofsymptoms of epilepsy, neurodegenerative diseases, heart disease and typeII diabetes. Known methods of accessing the energy and health benefitsketones provide are often not effective, and all solutions, regardlessof efficacy, are not well tolerated and therefore not readily availableto most of the general population.

The most common method of elevating circulating ketone levels is throughdiet-depriving the body of glucose by fasting or adhering to a ketogenicdiet such that metabolism switches from using glucose to ketonesproduced endogenously from fatty acids. These diets can be difficult toadhere to on a long-term basis and are impractical for most people.

Exogenous sources of ketones including ingestible ketone bodies andtheir precursors may prevent the need for extended fasting or ketogenicdiets to elevate circulating ketone levels. However, each of the knowningestible ketone bodies also has drawbacks limiting their use.

D 1,3 butanediol for example, is a metabolic precursor toD-β-hydroxybutyrate (D-BHB) and may be used as source of calories.However, D 1,3 butanediol has an unpleasant bitter flavor preventing itfrom playing a significant role in the food supply.

Another example of an ingestible ketone body precursor is racemic 1,3-butanediol. Racemic 1, 3-butanediol can cause unwanted side effects.For example, non-physiological isomers, such as (L)-β-hydroxybutyratecan act as competitive inhibitors to ketone body transport. Ketone bodytransport across the blood-brain barrier is a limiting factor to ketonebody metabolism in the brain.

The ketone body D-beta hydroxybutyric acid is another source ofexogenous ketones. One of the well-known problems with betahydroxybutyric acid, however, is that it is very acidic. D-betahydroxybutyric acid has a pH similar to lemon juice of 2.5. Because ofthis acidity the quantity and concentration in which D-betahydroxybutyric acid may be used in ingestible form is limited. Directadministration of large quantities of D-β-hydroxybutyrate oracetoacetate in their acid form can result in acidosis following rapidabsorption from the gastrointestinal tract.

Ketone body concentrations may also be elevated by administering acyclic trimer of D-β-hydroxybutyrate (triolide) as a metabolic precursorfor D-β-hydroxybutyrate. However, the triolide is not efficientlyhydrolyzed by gastric enzymes and thus is poorly absorbed. This limitsits usefulness as a (R)-3-hydroxybutyrate precursor.

The acidity problem with D-BHB acid has been addressed in someapplications by combining D-BHB with sodium, magnesium, calcium andpotassium salts (D'Agostino, U.S. 2020/0268701A1). This approach doesn'tfully address the problem, however. While the salts address the acidityproblem, use of ketone salts is limited to very small nutritionally andtherapeutically irrelevant amounts due to the high accompanying saltload. In addition to the small dosage, the taste is also unpleasant.

Ketone ester compounds—another metabolic precursor—as disclosed in U.S.Pat. No. 8,642,654, avoid the salt load problem and can be administeredin high concentrations to induce ketosis. Ketone esters generally have atoxic flavor thus limiting their use as a supplement or therapeuticagent.

Thus, ingesting sufficient amounts of D-BHB in an acid or salt form toachieve ketosis is not viable due to the accompanying acid/salt load aswell as gastrointestinal side effects. Ingestion of such compounds isalso associated with sleep loss. Often, ingestion of commercialcompositions containing such ketone salt or ketone ester compounds failsto result in a sufficient plasma level increase. For example, ingestionof commercial compositions containing such ketone salt or ketone estercompounds often results in a 0.5 mM or lower increase in circulatingketone levels, which does not provide a cognitive or physical benefit.Often, ingestion of commercial compositions containing such ketone saltor ketone ester compounds is intolerable multiple times daily or for anextended number of days or weeks. As such, existing products areassociated with poor taste, poor bioavailability, poor tolerability, andside effects. Further, such existing ketone salt products providerelatively low amounts of ketone compounds at high cost, making theirbenefits, if any, too low relative to their cost.

There is a long-felt and unmet need to augment the food supply and makethe health benefits of ketones readily available to the mainstreammarket in a composition that efficiently induces ketosis withoutrestriction, is well-tolerated, and tastes good. Additionally, it wouldbe beneficial to have a composition that can be more cost-effective andmore efficient than prior methods of inducing ketosis.

SUMMARY OF THE INVENTION

Disclosed herein are novel combinations of (D)-β-hydroxybutyric acid,(D)-β-hydroxyvaleric acid, and (D)-1,3 butanediol and compositions thatinclude these components. Food and beverage products including a novelcombination of these compositions are also disclosed. These novelcompositions can taste better, avoid acidity issues, and thus can resultin superior palatability when compared with other exogenous ketonecompositions. Moreover, the combinations disclosed herein can have agreater efficacy than other exogenous ketone compositions. Whenadministered to a subject, these combinations of (D)-β-hydroxybutyricacid, (D)-β-hydroxyvaleric acid, and (D)-1,3 butanediol exhibitproperties that are greater than administration of either constituentindividually. Thus, disclosed examples permit achieving nutritional andtherapeutic benefits of circulating ketone bodies using less materialthan would otherwise be required. Furthermore, drawbacks limiting use ofketone body precursors may be avoided. These benefits can be obtainedwhile providing a better tasting compound that is likely to be bettertolerated by the person consuming the composition.

Examples disclosed herein can induce functional ketosis to a greaterextent than known compositions. Ketone bodies have been found to have arange of potential benefits, from treatment of diabetes andneurodegenerative disease symptoms, to enhanced cognitive health andendurance performance in athletes. Examples disclosed herein have thepotential to yield higher net elevation of circulating ketones over timein an individual. When administered in therapeutically effectiveamounts, the disclosed combination of compositions can produce a higherdegree of ketotic efficiency than other known ketone body supplements.

Also disclosed is a method of improving the flavor profile of a food orbeverage product including ketone bodies. The method can include adding(D)-1,3 butanediol to (D)-β-hydroxybutyric acid in a specific ratio asdisclosed herein. Optionally, (D)-β-hydroxyvaleric acid may also beincluded in the composition. The method may include using the (D)-1,3butanediol as a solvent for flavorings. For example, a source offlavoring such as fruit may be added to (D)-1,3, butanediol. The fruitmay be added to the (D)-1,3 butanediol for a predetermined amount oftime to allow the flavorings to enter a solution. In one example, thefruit may be freeze dried fruit. After a desired amount of flavoring hasentered the solution, the solution can be filtered to remove fiber,pulp, and other undesirable components. This resulting solution can thenbe added to (D)-β-hydroxybutyric acid. In another example, the resultingflavored solution including (D)-1,3 butanediol may be added to(D)-β-hydroxybutyric acid and (D)-β-hydroxyvaleric acid. According tocertain embodiments, a beverage may be created by including asubstantial amount of consumable liquid, such as water. A beverage mayinclude carbonation. A food product may be produced by including anamount of a consumable (edible) solid, liquid, or gel. In some aspects,the product may include a slowly dissolving or slowly digesting matrix.In some aspects a slowly digesting matrix may include fibers andcarbohydrates having a glycemic index of less than 70, e.g., 40 to 65,62, 60, 57, 55 or lower.

Other features and characteristics of the subject matter of thisdisclosure, as well as the methods of operation, functions of relatedelements of structure and the combination of parts, and economies ofmanufacture, will become more apparent upon consideration of thefollowing description and the appended claims, all of which form a partof this specification.

BRIEF DESCRIPTION OF THE DRAWINGS

Various features of examples and embodiments in accordance with theprinciples described herein may be more readily understood withreference to the following detailed description taken in conjunctionwith the accompanying drawings, where like reference numerals designatelike structural elements, and in which:

FIG. 1 represents the results of administration of (D)-β-hydroxybutyricacid, (D)-β-hydroxyvaleric acid and (D)-1,3 butanediol over the courseof a 60-minute period in various ratios in a subject at rest; and

FIG. 2 represents the expected ketosis for a subject at rest with a 0.13g/kg dose of (D)-β-hydroxybutyric acid, (D)-β-hydroxyvaleric acid and(D)-1,3 butanediol over time for the periods shown.

FIG. 3 represents a flow-chart of a process of improving the flavoringof a food or beverage including a ketone body according to one example.

DETAILED DESCRIPTION

While aspects of the subject matter of the present disclosure may beembodied in a variety of forms, the following description is merelyintended to disclose some of these forms as specific examples of thesubject matter encompassed by the present disclosure. Accordingly, thesubject matter of this disclosure is not intended to be limited to theforms or embodiments so described.

Concentrations, amounts, and other numerical data may be expressed orpresented herein in a range format. It is to be understood that such arange format is used merely for convenience and brevity and thus shouldbe interpreted flexibly to include not only the numerical valuesexplicitly recited as the limits of the range, but also to include allthe individual numerical values or sub-ranges encompassed within thatrange as if each numerical value and sub-range is explicitly recited. Asan illustration, a numerical range of “about 0.01 to 2.0” should beinterpreted to include not only the explicitly recited values of about0.01 to about 2.0, but also include individual values and sub-rangeswithin the indicated range. Thus, included in this numerical range areindividual values such as 0.5, 0.7, and 1.5, and sub-ranges such as from0.5 to 1.7, 0.7 to 1.5, and from 1.0 to 1.5, etc. Furthermore, such aninterpretation should apply regardless of the breadth of the range orthe characteristics being described. Additionally, it is noted that allpercentages are in weight, unless specified otherwise.

In understanding the scope of the present disclosure, the terms“including” or “comprising” and their derivatives, as used herein, areintended to be open ended terms that specify the presence of the statedfeatures, elements, components, groups, integers, and/or steps, but donot exclude the presence of other unstated features, elements,components, groups, integers and/or steps. The foregoing also applies towords having similar meanings such as the terms “including”, “having”and their derivatives. The term “consisting” and its derivatives, asused herein, are intended to be closed terms that specify the presenceof the stated features, elements, components, groups, integers, and/orsteps, but exclude the presence of other unstated features, elements,components, groups, integers and/or steps. The term “consistingessentially of”, as used herein, is intended to specify the presence ofthe stated features, elements, components, groups, integers, and/orsteps as well as those that do not materially affect the basic and novelcharacteristic(s) of features, elements, components, groups, integers,and/or steps. It is understood that reference to any one of thesetransition terms (i.e. “comprising,” “consisting,” or “consistingessentially”) provides direct support for replacement to any of theother transition term not specifically used. For example, amending aterm from “comprising” to “consisting essentially of” would find directsupport due to this definition.

As used herein, the terms “about” and “approximately” are used toprovide flexibility to a numerical range endpoint by providing that agiven value may be “a little above” or “a little below” the endpoint.The degree of flexibility of this term can be dictated by the particularvariable and would be within the knowledge of those skilled in the artto determine based on experience and the associated description herein.For example, in one aspect, the degree of flexibility can be withinabout ±10% of the numerical value. In another aspect, the degree offlexibility can be within about ±5% of the numerical value. In a furtheraspect, the degree of flexibility can be within about ±2%, ±1%, or±0.05%, of the numerical value.

As used herein, a plurality of compounds, elements, or steps may bepresented in a common list for convenience. However, these lists shouldbe construed as though each member of the list is individuallyidentified as a separate and unique member. Thus, no individual memberof such list should be construed as a de facto equivalent of any othermember of the same list solely based on their presentation in a commongroup without indications to the contrary.

Furthermore, certain compositions, elements, excipients, ingredients,disorders, conditions, properties, steps, or the like may be discussedin the context of one specific embodiment or aspect or in a separateparagraph or section of this disclosure. It is understood that this ismerely for convenience and brevity, and any such disclosure is equallyapplicable to and intended to be combined with any other embodiments oraspects found anywhere in the present disclosure and claims, which allform the application and claimed invention at the filing date.

As used herein, the phrase “substantially no” may refer to a compositioncontaining less than 1, 0.9, 0.8, 0.7, 0.6, 0.5, 0.4, 0.3, 0.2, 0.1,0.09, 0.08, 0.07, 0.06, 0.05, 0.04, 0.03, 0.02, or 0.01 wt % of aspecified ingredient. In some aspects, the phrase “substantially no” mayrefer to a composition containing trace amounts of a specifiedingredient. In some aspects, the phrase “substantially no” may refer toa composition containing a specified ingredient below a level ofdetection.

In some aspects, the present disclosure includes using anenantiomerically pure form of a compound, e.g., greater than 95, 96, 97,98, 99, or 99.5% enantiomerically pure.

Throughout this description, the preferred embodiments and examplesprovided herein should be considered as exemplary, rather than aslimitations, of the present invention.

In a first aspect, the present disclosure provides a combination of(D)-β-hydroxybutyric acid (“D-BHB”) and (D)-1,3 butanediol (“D-1,3BD. Ina further aspect, the present disclosure provides a combination ofD-BHB, (D)-β-hydroxyvaleric acid (“D-BHV”), and D-1,3BD. Numerousnon-limiting examples providing exemplary proportions of these compoundsare provided. These combinations and compositions containing suchcombinations may be prepared as food and beverage products for humanconsumption, thereby providing a dietary source of exogenous ketones.The resulting mixture can exhibit reduced acidity, better flavoring, andreduce or avoid the need to add additional salts to the composition toimprove palatability. Moreover, the combinations disclosed herein canhave a greater efficacy than other exogenous ketone compositions. Whenadministered to a subject, the disclosed combinations of D-BHB andD-1,3BD and the disclosed combinations of D-BHB, D-BHV, and D-1,3BDexhibit an increase in blood ketones that is greater than administrationof either constituent individually. Thus, the disclosed examples permitachieving nutritional and therapeutic benefits of sufficiently highcirculating ketone bodies using less material than would otherwise berequired.

As used herein, the terms “administer” and “administration” will includeself-administration, ingestion, or consumption by a subject. In otherwords, the terms will include methods that result in consumption of thedisclosed products by a subject. As such, methods of the presentdisclosure will include making, using, selling, offering for sale,importing, or exporting any of the products or compositions of thepresent disclosure intended for consumption or use in producing aconsumable product.

In one aspect, the present disclosure provides a composition having 25%to 85% by weight of (D)-β-hydroxybutyric acid and 15% to 75% by weightof (D)-1,3 butanediol. In one aspect, the present disclosure provides acomposition having 25% to 85% by weight of a mixture of(D)-β-hydroxybutyric acid and (D)-β-hydroxyvaleric acid and 15% to 75%by weight of (D)-1,3 butanediol. In one aspect, the molar ratio of(D)-β-hydroxybutyric acid to (D)-β-hydroxyvaleric acid may be between1.0 to 0.01 and 0.7 to 0.3. In one aspect, the present disclosureprovides a composition having (D)-β-hydroxybutyric acid and (D)-1,3butanediol in a molar ratio range of 3:7 to 7:3. In one aspect, thepresent disclosure provides a composition having (D)-β-hydroxybutyricacid and (D)-1,3 butanediol in a molar ratio range of 4:6 to 6:4. In oneaspect, the present disclosure provides a composition having(D)-β-hydroxybutyric acid and (D)-1,3 butanediol in a 1:1 molar ratio.In one aspect, the present disclosure provides a composition having 25%to 75% by molar of a mixture of (D)-β-hydroxybutyric acid and(D)-β-hydroxyvaleric acid and 25% to 75% by weight of (D)-1,3butanediol. In one aspect, the present disclosure provides a compositionhaving 35% to 70% by weight of a mixture of (D)-β-hydroxybutyric acidand (D)-β-hydroxyvaleric acid and 30% to 65% by weight of (D)-1,3butanediol. In one aspect, the present disclosure provides a compositionhaving 45% to 55% by weight of a mixture of (D)-β-hydroxybutyric acidand (D)-β-hydroxyvaleric acid and 55% to 45% by weight of (D)-1,3butanediol. In one aspect, the present disclosure provides a compositionhaving 48% to 52% by weight of a mixture of (D)-β-hydroxybutyric acidand (D)-β-hydroxyvaleric acid and 48% to 52% by weight of (D)-1,3butanediol.

In one aspect, a composition, beverage or food product of the presentdisclosure may contain at least 5, 10, 20, 30, 40, 50, 60, 70, 80, or90% of the D)-β-hydroxybutyric acid, the (D)-β-hydroxyvaleric acid, orboth, in the form of a magnesium salt, potassium salt, sodium salt,calcium salt, or combination thereof. In some aspects, the composition,beverage or food product of the present disclosure may contain up to 50%of the D)-β-hydroxybutyric acid, the (D)-β-hydroxyvaleric acid, or both,in the form of a magnesium or potassium salt. In some aspects, thecomposition, beverage or food product of the present disclosure maycontain up to 30% of the D)-β-hydroxybutyric acid, the(D)-β-hydroxyvaleric acid, or both, in the form of a calcium salt. Insome aspects, the composition, beverage or food product of the presentdisclosure may contain up to 60% of the D)-β-hydroxybutyric acid, the(D)-β-hydroxyvaleric acid, or both, in the form of a combination ofmagnesium, potassium, and/or calcium salts.

In another aspect, the present disclosure provides a method andcomposition for increasing plasma levels of ketone bodies in a humansubject by 30, 40, 50%, 60% or more compared to administration of anequivalent amount by weight of (D)-β-hydroxybutyrate or (D)-1,3butanediol alone by administering the compositions of the presentdisclosure.

In another aspect, the present disclosure provides a method andcomposition for inducing a D-BHB plasma level increase of at least 1.4mM within 2 hours by administering the compositions of the presentdisclosure.

In another aspect, the present disclosure provides a method andcomposition for inducing a D-BHB plasma level increase of at least 1.5mM within 2 hours by administering the compositions of the presentdisclosure.

In another aspect, the present disclosure provides a method andcomposition for inducing a D-BHB plasma level increase of at least 2.0mM within 2 hours by administering the compositions of the presentdisclosure.

In another aspect, the present disclosure provides a method andcomposition for maintaining a D-BHB plasma level increase of at least1.4 mM for 2.5 hours by administering the compositions of the presentdisclosure.

In another aspect, the present disclosure provides a method andcomposition for maintaining a D-BHB plasma level increase of at least1.4 mM for 3 hours by administering the compositions of the presentdisclosure.

In another aspect, the present disclosure provides a method andcomposition for maintaining a D-BHB plasma level increase of at least1.4 mM for 3.5 hours by administering the compositions of the presentdisclosure.

In another aspect, the present disclosure provides a method andcomposition for maintaining a D-BHB plasma level increase of at least1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2 mM for 2, 2.5, 3, 3.5, or 4 hours byadministering the compositions of the present disclosure.

In another aspect, the present disclosure provides a method andcomposition that is tolerable and sufficiently palatable for daily useby a human subject for at least 12, 26, 52 weeks, or longer byadministering the compositions of the present disclosure.

In another aspect, the present disclosure provides a method andcomposition that is tolerable and sufficiently palatable for use 1, 2,3, 4, 5, or 6 times daily by a human subject for at least 12, 26, 52weeks, or longer by administering the compositions of the presentdisclosure.

In another aspect, the present disclosure provides a method of reducingor avoiding gastrointestinal side effects associated with ingestion ofsalts or esters of D-BHB and D-1,3BD or compositions containing D-BHB orD-1,3BD as single agents by administering the compositions of thepresent disclosure.

In another aspect, the present disclosure provides a method of reducingor avoiding sleep loss associated with ingestion of salts or esters ofD-BHB and D-1,3BD or compositions containing D-BHB or D-1,3BD as singleagents by administering the compositions of the present disclosure.

In another aspect, the present disclosure provides a method ofincreasing slow wave sleep (SWS) duration by at least 10, 20, 30, 40, or50% relative to compositions and methods of ingestion of salts or estersof D-BHB and D-1,3BD or compositions containing D-BHB or D-1,3BD assingle agents, by administering the compositions of the presentdisclosure.

In another aspect, the present disclosure provides a method ofincreasing rapid eye movement (REM) sleep duration by at least 10, 20,30, 40, or 50% relative to compositions and methods of ingestion ofsalts or esters of D-BHB and D-1,3BD or compositions containing D-BHB orD-1,3BD as single agents, by administering the compositions of thepresent disclosure.

Example 1

According to a first example, a composition includes approximately 85%D-BHB and approximately 15% D-1,3BD. In this example, there may besubstantially no D-BHV present in the composition.

Example 2

According to a second example, a composition includes approximately 59%D-BHB, approximately 26% D-BHV, and approximately 15% D-1,3BD. Thisexample is similar to Example 1 except that D-BHV is present instead ofsome of the D-BHB in the resulting composition.

Example 3

According to a third example, a composition includes approximately 25%D-BHB and approximately 75% D-1,3BD. In this example, there may besubstantially no D-BHV present in the composition.

Example 4

According to a fourth example, a composition includes approximately 17%D-BHB, approximately 8% D-BHV, and 75% D-1,3BD. This example is similarto Example 3 except that D-BHV is present instead of some of the D-BHBin the resulting composition.

Example 5

According to a fifth example, a composition includes approximately 46%D-BHB, approximately 4% D-BHV, and approximately 50% D-1,3BD.

Example 6

According to a sixth example, a composition includes approximately 40%D-BHB, approximately 10% D-BHV, and approximately 50% D-1,3BD.

Example 7

According to a seventh example, a composition includes approximately 23%D-BHB, approximately 2% D-BHV, and approximately 75% D-1,3BD.

Example 8

According to an eighth example, a composition includes approximately 20%D-BHB, approximately 5% D-BHV, and approximately 75% D-1,3BD.

Example 9

According to a ninth example, a composition includes approximately 64%D-BHB, approximately 1% D-BHV, and approximately 35% D-1,3BD.

Example 10

According to a tenth example, a composition includes approximately 59%D-BHB, approximately 6% D-BHV, and approximately 35% D-1,3BD.

Example 11

According to a eleventh example, a composition includes approximately44% D-BHB, approximately 1% D-BHV, and approximately 55% D-1,3BD.

Example 12

According to a twelfth example, a composition includes approximately 41%D-BHB, approximately 4% D-BHV, and approximately 55% D-1,3BD.

Example 13

According to a thirteenth example, a composition includes approximately84% D-BHB, approximately 1% D-BHV, and approximately 15% D-1,3BD.

Example 14

According to a fourteenth example, a composition includes approximately72% D-BHB, approximately 13% D-BHV, and approximately 15% D-1,3BD.

Example 15

According to a fifteenth example, a composition includes approximately59% D-BHB, approximately 1% D-BHV, and approximately 40% D-1,3BD.

Example 16

According to a sixteenth example, a composition includes approximately51% D-BHB, approximately 9% D-BHV, and approximately 40% D-1,3BD.

In accordance with examples 1 to 4, the weight percentage of D-BHB andD-BHV can range between approximately 25% and approximately 85%. Thepercentage by weight of D-BHB to D-BHV may be varied within this range.The amount of D-BHV by weight of the composition may range, for example,between substantially 0% to approximately 26% D-BHV. Additionally, inthese examples, the percentage by weight of D-1,3BD can range fromapproximately 15% to approximately 75% by weight.

In accordance with examples 5 to 8, the weight percentage of D-BHB andD-BHV can range between approximately 25% and approximately 50%. Thepercentage by weight of D-BHB to D-BHV may be varied within this range.The amount of D-BHV by weight of the composition may range, for example,between approximately 2% to approximately 10%. Additionally, in theseexamples, the percentage by weight of D-1,3BD can range fromapproximately 50% to about 75% by weight.

In accordance with examples 9 to 12, the weight percentage of D-BHB andD-BHV can range between approximately 45% and approximately 65%. Thepercentage by weight of D-BHB to D-BHV may be varied within this range.The amount of D-BHV by weight of the composition may range, for example,between approximately 1% to approximately 6%. Additionally, in theseexamples, the percentage by weight of D-1,3BD can range fromapproximately 35% to about 55% by weight.

In accordance with examples 13 to 16, the weight percentage of D-BHB andD-BHV can range between approximately 60% and approximately 85%. Thepercentage by weight of D-BHB to D-BHV may be varied within this range.The amount of D-BHV by weight of the composition may range, for example,between approximately 1% to approximately 9%. Additionally, in theseexamples, the percentage by weight of D-1,3BD can range fromapproximately 15% to about 40% by weight.

In accordance with each of the examples above, a general exemplarycomposition disclosed herein includes between approximately 15% toapproximately 85% D-BHB, between substantially no D-BHV to approximately26% D-BHV, and between approximately 15% to approximately 75% D-1,3BD.Various examples of this general composition are given, but are notintended to be presented to the exclusion of compositions within thevarious disclosed ranges.

The administration of examples presented herein result in an increase inthe circulating level of ketones in a human subject at rest that isgreater than would result from the administration of(D)-β-hydroxybutyrate or (D)-1,3 butanediol alone over a duration of,for example, 120 minutes. Some examples include administration of acombination of D-BHB, D-BHV, and D-1,3BD in a therapeutically effectiveamount such that the rate change of circulating ketones in the blood ofa human subject at rest is faster than the administration of anequivalent amount of either D-BHB or D-1,3BD administered alone. In oneexample, this includes the administration of a composition including amixture of 45% D-BHB and 55% D-1,3BD. In one example, this includes theadministration of a composition including a mixture of 43.2%% D-BHB,1.8% D-BHV and 55% D-1,3BD. In another example, this includes theadministration of a composition including a mixture of 52.8% DBHB, 2.2%D-BHV, and 45% D-1,3BD. In another example, this includes theadministration of at composition including a mixture of 62.4% D-BHB,2.6% D-BHV, and 35% D-1,3BD.

FIG. 1 shows the results of administration of D-BHB, D-BHV, and D-1,3BDover the course of a 60-minute period in various ratios in a subject atrest. Examples include using a composition including D-BHB, D-BHV, andD-1,3BD in a subject at rest. The ketotic efficiency represents the netelevation of circulating ketones a ketone supplement affects over timein an individual. Ketotic efficiency may be represented as:

Σ_(t=0) ^(n)(mMol/L)/(g/kg)*t

where mMol/L is the concentration of circulating β-hydroxybutyrate inthe blood, g is the total dose of the combined D-BHB, D-BHV, andD-1,3,BD in grams, kg is the mass of the individual in kilograms, and tis an increment of time in minutes.

The ketotic efficiency of the D-BHB, D-BHV, and D-1,3BD blend measuredover of one hour in this exemplary study is 43% to 104% greater than theadministration of pure (D)-1,3 butanediol or pure (D)-β-hydroxybutyricacid alone, respectively. While this example pertains to a fastedsubject at rest, the relative utility of blended vs pure constituentshas also been observed in fed and active subjects.

As illustrated by the examples of FIG. 1, these exemplary compositionscan advantageously elevate circulating ketones by approximately twotimes greater than other known compositions. Such a composition cansustain ketonemia for longer than either D-BHB or D-1,3BD can wheningested alone by a subject of a given weight as shown by the 100% line(i.e., contains D-BHB, but not D-1,3BD) and the 0% line (i.e., containsonly D-1,3BD, but not D-BHB).

As shown in the following table, the increase in circulating ketonelevel with a 10 g dose in three human subjects at rest was maximal atbetween 45-55% D-BHB in the tested compositions.

% D-BHB Acid Max change in mMol/L 100%  0.9 85% 1.3 65% 1.3 55% 1.4 45%1.4 25% 1  0% 0.8

FIG. 2 represents the expected ketosis for a person at rest with a 0.13g/kg dose of (D)-β-hydroxybutyric acid, (D)-β-hydroxyvaleric acid, and(D)-1,3 butanediol over time for the periods shown. For instance, basedon the measured plasma levels illustrated in FIG. 1, it can be concludedthat administration of 100% D-1,3BD does not cause a prolonged rise ofblood ketone levels. A similar result was obtained upon administrationof 100% D-BHB. Administration of examples in accordance with the presentdisclosure are expected to cause efficient, prolonged rises incirculating blood ketone levels in a manner that is unexpected based onthe current literature. As shown in the following table, the highestefficiency at both 1 and 2 hours post-administration was obtained at 45%D-BHB+D-BHV (0.96:0.04) to 55% D-1,3BD and the lowest efficiency wasobserved when administering D-BHB or D-1,3BD alone.

Concentration of 1 hour ketotic 2 hours ketotic DBHB + DBHV in aefficiency efficiency compositing containing (kg*Mmol*min/ (kg*Mmol*min/DBHB + DBHV and D-1,3BD g*L) g*L) 100%  335 566 85% 427 739 65% 497 78055% 520 774 45% 543 826 25% 381 739  0% 266 462

As demonstrated herein, the combination of the present disclosure safelyinduces ketosis more rapidly than previously thought possible. Forexample, U.S. Pat. No. 9,138,420 shows that a peak concentration ofblood concentrations of (D)-β-hydroxybutyrate produced by consuming acombination of (D/L)-β-hydroxybutyrate salt and MCT (medium chaintriglycerides) oil required up to 3 hours.

The present disclosure includes mixing D-BHB, D-BHV, and D-1,3BD in afood or beverage product. For example, any of the compositions accordingto the examples, discussed earlier, may be included within a beverage orfood product. Still further examples include the administration of thedisclosed compositions of D-BHB, D-BHV, and D-1,3BD as a nutritionalsupplement to induce ketonemia. Still further examples include theadministration of the disclosed compositions including D-BHB, D-BHV, andD-1,3BD as a nutritional supplement to increase cognitive and physicalendurance and performance, reduce food cravings, and increase appetitecontrol.

An example of a method includes administering a composition to a humansubject in a beverage or food product. In one aspect, the beverage orfood product may be designed to be consumed in one sitting rather thanover a prolonged period. The exemplary compositions described in thenon-limiting examples and other disclosures provided herein may be usedin such beverage or food products.

In some aspects, the present disclosure involves a unit dosagecontaining about 5 grams or more of the combination of D-BHB, D-BHV, andD-1,3BD of the present disclosure. In some aspects, the presentdisclosure involves a unit dosage containing 5-50, 6 to 49, 7 to 48, 8to 47, 8 to 46, 9 to 45, 10 to 44, 11 to 43, 12 to 42, 13 to 40, 14 to35, 15 to 30, 16-25, or 18 to 22 grams of the combination of D-BHB,D-BHV, and D-1,3BD of the present disclosure. In some aspects, thepresent disclosure includes a composition or method for inducing andmaintaining ketonemia or ketosis by ingesting at least 10 grams of thecombination of D-BHB, D-BHV, and D-1,3BD of the present disclosure daily(e.g., 1, 2, 3, 4, 5, 6, or more times per day). In some aspects, thepresent disclosure includes a composition or method for inducing andmaintaining ketonemia or ketosis by ingesting at least 10 grams of thecombination of D-BHB, D-BHV, and D-1,3BD of the present disclosureweekly (e.g., 5, 6, 7, 8, 9, 10, 12, 14, 21, 28 or more times per week).In some aspects, the present disclosure includes a composition or methodfor inducing and maintaining ketonemia or ketosis by ingesting at least10 grams of the combination of D-BHB, D-BHV, and D-1,3BD of the presentdisclosure every 2, 3, 4, or 5 hours. In some aspects, the presentdisclosure includes a composition or method for inducing and maintainingketonemia or ketosis by ingesting at least 10 grams of the combinationof D-BHB, D-BHV, and D-1,3BD of the present disclosure at each meal. Insome aspects, the present disclosure includes a composition or methodfor inducing and maintaining ketonemia or ketosis by ingesting at least10 grams of the combination of D-BHB, D-BHV, and D-1,3BD of the presentdisclosure before, during, or after a fasted state of at least 6, 8, 10,or 12 hours.

The present disclose includes a total daily dosage of 50, 60, 70, 80,90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 grams ofthe combination of D-BHB, D-BHV, and D-1,3BD of the present disclosure.

In some aspects, the combination of D-BHB, D-BHV, and D-1,3BD of thepresent disclosure is administered at a dosage of 0.10 to 1 g/kg, 0.12to 0.8 g/kg, 0.13 to 0.7 g/kg, 0.14 to 0.6 g/kg, 0.15 to 0.5 g/kg perunit dosage. In some aspects, the combination of D-BHB, D-BHV, andD-1,3BD of the present disclosure is administered at a dosage of 0.30 to3 g/kg, 0.4 to 2.5 g/kg, 0.5 to 2 g/kg, 0.75 to 1.5 g/kg, 0.8 to 1 g/kgper day.

In some aspects, the present disclosure includes compositions forreducing or avoiding side effects such as acidosis and gastrointestinaldistress upon ingestion of D-BHB, D-BHV, and D-1,3BD.

In some aspects, the present disclosure includes compositions forreducing or avoiding side effects such as intoxication from1,3-butanediol by use of the combination of D-BHB, D-BHV, and D-1,3BD ofthe present disclosure.

According to other methods, a composition including approximately 15% toapproximately 85% D-BHB, between substantially no D-BHV to approximately26% D-BHV, and between approximately 15% to approximately 75% D-1,3BD,such as any of the compositions set forth in the examples (or variantsthereof) is administered to a human subject to increase levels ofcirculating ketones in the blood of the subject. In such compositions,the proportion of D-BHB to D-BHV can be between 1.0 to 0 and 0.7 to 0.3,0.99 to 0.01, 0.98 to 0.02, 0.97 to 0.03, 0.96 to 0.04, 0.95 to 0.05,0.9 to 0.1, 0.85 to 0.15, 0.8 to 0.2, or 0.75 to 0.25. Such compositionsmay be administered using specific carriers, e.g., as described belowand illustrated in several examples.

According to another example, the individual constituent components ofapproximately 15% to approximately 85% D-BHB, between substantially noD-BHV to approximately 26% D-BHV, and between approximately 15% toapproximately 75% D-1,3BD may be taken in rapid succession, such that,for example, D-BHB is taken first, D-BHV is taken second, and D-1,3,BDis taken third. According to one example, the D-BHB and D-BHV may betaken first, and the D-1,3BD may be taken second. The D-BHV and D-BHBmay be taken simultaneously as a single mixture of these compounds inappropriate amounts. In another example, the D-1,3BD may be taken first,and the D-BHB and D-BHV may be taken second. In other examples, oneportion of the composition may be taken 2, 3, or 5 minutes before theother portion of the composition.

In one aspect, the present disclosure involves the described compounds,i.e., (D)-β-hydroxybutyric acid, (D)-β-hydroxyvaleric acid, and/or(D)-1,3 butanediol, that are not in the form of a salt (e.g., not asodium, magnesium, calcium and/or potassium salt). In one aspect, thepresent disclosure involves the described compounds, i.e.,(D)-β-hydroxybutyric acid, (D)-β-hydroxyvaleric acid, and/or (D)-1,3butanediol, that are not in the form of an ester. In one aspect, thepresent disclosure involves compositions comprising (D)-β-hydroxybutyricacid, (D)-β-hydroxyvaleric acid, and/or (D)-1,3 butanediol in abuffer-free composition. In one aspect, the present disclosure involvescompositions comprising (D)-β-hydroxybutyric acid, (D)-β-hydroxyvalericacid, and/or (D)-1,3 butanediol in a lactose-free composition. In oneaspect, the present disclosure involves compositions comprising(D)-β-hydroxybutyric acid, (D)-β-hydroxyvaleric acid, and/or (D)-1,3butanediol in a gluten-free composition. In one aspect, the presentdisclosure involves compositions comprising (D)-β-hydroxybutyric acid,(D)-β-hydroxyvaleric acid, and/or (D)-1,3 butanediol in a soy-freecomposition. In one aspect, the present disclosure involves compositionscomprising (D)-β-hydroxybutyric acid, (D)-β-hydroxyvaleric acid, and/or(D)-1,3 butanediol in a caffeine-free composition. In one aspect, thepresent disclosure involves compositions comprising (D)-β-hydroxybutyricacid, (D)-β-hydroxyvaleric acid, and/or (D)-1,3 butanediol in acarbohydrate-free composition. In one aspect, the present disclosureinvolves compositions comprising (D)-β-hydroxybutyric acid,(D)-β-hydroxyvaleric acid, and/or (D)-1,3 butanediol in a compositionfree of 3-hydroxybutyl-β-hydroxybutyrate. In one aspect, the presentdisclosure involves compositions comprising (D)-β-hydroxybutyric acid,(D)-β-hydroxyvaleric acid, and/or (D)-1,3 butanediol in a compositionfree of 3-hydroxybutyl-3-hydroxy-ethyl butyrate. In one aspect, thepresent disclosure involves compositions comprising (D)-β-hydroxybutyricacid, (D)-β-hydroxyvaleric acid, and/or (D)-1,3 butanediol in acomposition free of 3-hydroxybutyl-3-hydroxy-butanoate. In one aspect,the present disclosure involves compositions comprising(D)-β-hydroxybutyric acid, (D)-β-hydroxyvaleric acid, and/or (D)-1,3butanediol in a composition free of ketone ester. In one aspect, thepresent disclosure involves compositions comprising (D)-β-hydroxybutyricacid, (D)-β-hydroxyvaleric acid, and/or (D)-1,3 butanediol in acomposition free of acetoacetate.

In one aspect, the present disclosure involves compositions comprising(D)-β-hydroxybutyric acid, (D)-β-hydroxyvaleric acid, and/or (D)-1,3butanediol in a composition free of the following compound D betahydroxybutyrate, DL 1,3-butanediol ester.

In one aspect, the present disclosure involves compositions comprising(D)-β-hydroxybutyric acid, (D)-β-hydroxyvaleric acid, and/or (D)-1,3butanediol in a sugar-free composition. In one aspect, the presentdisclosure involves compositions comprising (D)-β-hydroxybutyric acid,(D)-β-hydroxyvaleric acid, and/or (D)-1,3 butanediol in a compositionfree of polyesters of (D)-β-hydroxybutyric acid, (D)-β-hydroxyvalericacid, and/or (D)-1,3 butanediol. In one aspect, the present disclosureinvolves compositions comprising (D)-β-hydroxybutyric acid,(D)-β-hydroxyvaleric acid, and/or (D)-1,3 butanediol in a compositionfree of D ethyl 3-hydroxybutyrate. In one aspect, the present disclosureinvolves compositions comprising (D)-β-hydroxybutyric acid,(D)-β-hydroxyvaleric acid, and/or (D)-1,3 butanediol in a compositionfree of medium chain triglycerides. In one aspect, the presentdisclosure involves compositions comprising (D)-β-hydroxybutyric acid,(D)-β-hydroxyvaleric acid, and/or (D)-1,3 butanediol in a compositionfree of medium chain fatty acids. In one aspect, the present disclosureinvolves compositions comprising (D)-β-hydroxybutyric acid,(D)-β-hydroxyvaleric acid, and/or (D)-1,3 butanediol in a compositionfree of esters of medium chain fatty acids.

In one aspect, the present disclosure involves compositions comprising(D)-β-hydroxybutyric acid, (D)-β-hydroxyvaleric acid, and/or (D)-1,3butanediol in combination with a sugar alcohol. In one aspect, thepresent disclosure involves compositions comprising (D)-β-hydroxybutyricacid, (D)-β-hydroxyvaleric acid, and/or (D)-1,3 butanediol incombination with erythritol, sorbitol, mannitol, xylitol, aspartame,stevia glycosides, allulose, monk fruit (also referred to as monk fruitextract), and similar sweeteners having zero or low calories. Asweetener can be “low-calorie”, i.e., it imparts desired sweetness whenadded to a sweetenable composition (such as, for example, as beverage)and has less than 40 calories per 8 oz serving. A sweetener can be“zero-calorie”, i.e., it imparts desired sweetness when added to asweetenable composition (such as, for example, a beverage) and has lessthan 5 calories per 8 oz. serving, preferably 0 calories per 8 oz.serving.

Compositions based on the above examples may be mixed with a carriercomprising a food or beverage product as illustrated by the examplesbelow. The present disclosure includes products including, but notlimited to protein bars, nutritional and sports beverages, fruit juice,zero calorie iced caffeinated beverages, snacks, tea beverages,carbonated beverages, energy gels, and alcoholic beverages. The presentdisclosure also includes fermented foods and beverages containing thecompositions described herein. The preferred compositions may becombined in foods or beverages that exhibit various nutritional criteriasuch as low-calorie foods and beverages for weight control, low calorieand low carbohydrate for facilitating weight control and/or weight loss,low carbohydrate and/or high fat for those following a ketogenic diet,and high carbohydrate and/or high protein for athletes.

A method of improving the flavor profile of a food or beverage productincluding ketone bodies includes combining D-1,3BD with D-BHB andoptionally D-BHV to achieve a composition that can improve the taste offood or beverage products designed to induce ketosis. An exemplarymethod is described with reference to the flowchart of FIG. 3. Themethod can include providing a predetermined amount of D-1,3BD (310).Next, a flavoring agent may be added to the D-1,3BD (320) to create asolution including the D-1,3BD and the desired flavoring. According toone example, the flavoring agent may be a natural flavoring agent suchas fruit. The fruit may be fresh fruit or may be freeze dried fruitaccording to certain examples. The flavoring agent may be added to theD-1,3BD for a predetermined time, where the predetermined time is a timesufficient to obtain a desired flavor profile from the flavor agent. Byadding the flavor agent to the D-1,3BD, the D-1,3BD may act as a solventand allow the flavorings, such as natural flavorings, to enter aresulting solution including the D-1,3BD. After a desired amount of timehas elapsed, the resulting solution may be filtered to remove unwantedparts of the flavoring agent such as pulp and fiber (330). Thisfiltration step (330) is optional and the degree of filtering may beadjusted such that some fiber or pulp may remain in the resultingfiltered solution.

After the filtered flavored D-1,3BD is produced (step 330), thatsolution is combined with D-BHB and optionally D-BHV to form a flavoredsolution of D-1,3,BD, D-BHB, and optionally D-BHV (step 340). Thecombination of the flavored D-1,3BD and D-BHB and optional D-BHVsubstantially improves the resulting flavors of D-1,3BD and D-BHB ontheir own, thus providing ketone bodies for use as additives to food andbeverage products (step 350). Those skilled in the art will appreciatethat certain of the steps may be combined. For example, step 340 may becombined with step 350. For example, water may be added to D-BHB beforethe filtered flavored D-1,3BD is added to it, thus forming a flavoredwater beverage when the flavored D-1,3BD is added to a solutionincluding a substantial portion of water and D-BHB (with or withoutD-BHV). In another illustrative example, the D-1,3BD may be in abeverage product, while the D-BHB and D-BHV may be in a food or asemi-liquid product that is to be consumed with the beverage or apredetermined period of time before or after the beverage. Permutationsof these combinations are possible and envisioned. Various combinationsof these examples may be made so long as the D-BHB, optional D-BHV, andD-1,3BD are administered closely enough in time to give rise to thebenefits of the ketotic efficiency observed and expected from theexamples described above.

Where a medicament or nutritional product of the invention is for use ina beverage, food, snack bar, gel or the like, it is convenient to use itin the form of a liquid or solid, preferably with a composition havingapproximately 15% to approximately 85% D-BHB, between substantially noD-BHV to approximately 26% D-BHV, and between approximately 15% toapproximately 75% D-1,3BD, including any of the examples, disclosures orcombinations thereof. The resulting compositions may be administered ina dosage of greater than about 0.02 g/kg and more preferably betweenabout 0.1 to about 0.9 g/kg.

The present invention will now be described further by way ofillustration only by reference to the following examples. Furtherembodiments falling within the scope of the invention will occur tothose skilled in the art in light of these. Each of these examples isexpected to increase blood ketone levels by about 1.5 mMol, sustainedfor approximately 30 minutes and tapering over the course of 3 hours.For example, a person may achieve and maintain a ketone body level ofabout 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4, 2.5 mMor higher according to the methods of the present disclosure.

Example 1: Snack Bar

A 50% solution (D)-β-hydroxybutyric acid (36 g)+(D)-β-hydroxyvalericacid (4 g) (one having 48% D-BHB+2% D-BHV and 50% water) was stirredinto (D)-1,3 butanediol (20 g), peanut butter (118 g), maple syrup (30g), and vanilla extract (5 g) in a large mixing bowl. Dry ingredientswere then added, including 1¼ cups rolled oats, 2 tbsp chia and flaxseed blend, ¼ tsp salt, and ½ cup chocolate chips. The mixture was thencooled for 30 minutes, the dough portioned into 1 inch×3 inch bars on abaking sheet and baked at 175° F. for 60 minutes.

Example 2: Preparation of a Nutritional Beverage

The flavoring was prepared by adding freeze dried passion fruit (33 g)freeze dried pineapple (27 g) to (D)-1,3 butanediol (300G) and allowingto rest for 48 hours such that the fruit flavors are absorbed into thesolution. The solution is then filtered to remove the fiber and pulp.The flavoring was stirred into a solution of (D)-β-hydroxybutyric acid(288 g), (D)-β-hydroxyvaleric acid (12 g), and water (2173 g) using a 5gallon blending container and magnetic stirrer. Buffers and sweetenerswere then blended into the solution in the amounts of 20 g sodiumbicarbonate, 30 g potassium bicarbonate, and 420 g erythritol toconcentrate. Carbonated water was then added in the amount of 3310 g.The equipment used to make these products is not critical to theinvention and is being provided by way of example only. For example, animmersion blender may be used instead of a magnetic stirrer and mayachieve better results, particularly when making larger batches ofmaterial and to achieve better blending.

Example 3: Sports Energy and Hydration Beverage

A beverage was prepared by combining (D)-β-hydroxybutyric acid (40 g)with (D)-1,3 butanediol (44 g) and water (2,180 g). Sodium, potassiumand calcium salts of (D)-β-hydroxybutyric acid were then added to thesolution in the amounts of 4 g, 6 g and 6 g respectively. For theketogenic ingredients, this equates to molar proportions of 50%(D)-β-hydroxybutyric acid (10% in salt form), and 50% (D)-1,3butanediol. Flavorings and sweetener in the form of 6.6 g pineapple, 7.5g passionfruit and 110 g of erythritol were then added to the solution.

Example 4: Energy Gel

The following ingredients were mixed: 50% solution (D)-β-hydroxybutyricacid (60 g)+(D)-β-hydroxyvaleric acid (20 g) was stirred into (D)-1,3butanediol (40 g), brown rice syrup (½c), barley malt (½c), unrefinedcoconut oil (¼c), creamy peanut butter (¼c), and salt (1 tsp). Themixture was heated to between 130 and 150° F. over medium-low heat for3-5 minutes until the ingredients were well combined and achieved a lowviscosity. Warm water between (130 and 150° F.) (¼c) was added to thejar and mixed vigorously until well combined and no separation wasobserved.

Example 5: Alcoholic Beverage

A 45% solution (D)-β-hydroxybutyric acid (80 g) with(D)-β-hydroxyvaleric acid (20 g) (one having 44% D-BHB+11% D-BHV and 45%water) was stirred into (D)-1,3 butanediol (100 g). Water and flavoringwere then added to create a concentrate in the amounts of 243 g water,45 g monk fruit, and 6 g lime concentrate. Silver tequila was then addedin the amount of 450 ml.

Example 6: Iced Coffee Beverage

50% solution (D)-β-hydroxybutyric acid (14.4 g)+(D)-β-hydroxyvalericacid (0.6 g) (one having 48% D-BHB, 2% D-BHV and 50% water) was blendedinto (D)-1,3 butanediol (15 g) and MCT oil (15 g) using an emersionblender. The mixture was then added to 4 oz chilled espresso and 4 ozcold water.

Example 7: Extended Release Foods

Smoothies have been made to extend release of the ketones as follows:

Green Tart Ketone Smoothie

1 cup water

¼ cup coconut milk

4 romaine lettuce leaves

1 medium green apple

1 stalk celery

½ cup cucumber

1 handful watercress (or use spinach)

10 g D-1,3 butanediol

10 g D-b-hydroxybutyric acid and (D)-β-hydroxyvaleric acid

juice of 1 lime

Cherry Limeaid Ketone Smoothie

1 ripe nectarine or peach

1 heaping cup fresh or frozen cherries

¾ cup almond milk

1 medium lime

10 g D-1,3 butanediol

10 g D-b-hydroxybutyric acid and (D)-β-hydroxyvaleric acid

1 handful ice

Blueberry Breakfast Tart Smoothie

2¼ cups unsweetened almond milk

⅓ cup raw unsalted cashews, soaked

⅓ cup rolled oats

2 tablespoons pure maple syrup

½ teaspoon ground cinnamon

2 cups frozen blueberries

10 g D-1,3 butanediol

10 g D-b-hydroxybutyric acid and (D)-β-hydroxyvaleric acid

Gummies

227 g granulated sugar27 g sorbitol227 g corn syrup glucose,135 g D-BHB solution (one having 48% D-BHB, 2% D-BHV and 50% water)

90 g D-1,3BD

44 grams gelatin1.5 teaspoon candy flavoring

In one aspect, gummies can be made by the following steps:

-   -   Combine gelatin, D-1,3BD and the D-BHB solution in a heatproof        container. Stir gently to combine. Let sit for 5 minutes to give        your gelatin time to bloom.    -   Combine together the corn syrup, sugar, and sorbitol in a medium        saucepan. Stir gently to combine. Bring to a simmer on medium        heat.    -   Remove the mixture from the heat and stir in the D-BHB/gelatin        mixture with a spatula until gelatin is melted.    -   Let the mixture sit for 10 minutes and allow the mixture to        clear and foam to collect at the top. After 10 minutes the foam        should be able to be easily scooped off the surface with a        spoon.    -   Add any coloring or candy flavorings.    -   Pour mixture into candy molds.    -   Chill in the fridge for 24 hours.

Example 8: Avoiding Sleep Loss Side Effects

The following compositions are made into a consumable beverage andingested by a panel of human test subjects two times per day atbreakfast and after lunch each day for one week:

Concentration of DBHB + DBHV in a compositing containing DBHB + DBHV andComposition # D-1,3BD 1 100%  2 45% 3  0%

The panelists record their number of hours of sleep and sleep qualityduring each night of the test week. The panelists are then assigned to adifferent group during week two and record their number of hours ofsleep and sleep quality during each night of the second test week. Thepanelists are then assigned to a different group during week three andrecord their number of hours of sleep and sleep quality during eachnight of the third test week. The results are then compared both betweenthe same panelists during each week as well as an average of allpanelists for each composition. The comparisons show that ingestion ofcomposition 2 produces higher quality sleep (higher percentage SWS, REM)and longer sleep than compositions 1 and 2.

Example 9: Avoiding Gastrointestinal Side Effects

The following compositions are made into a consumable beverage andingested by a panel of human test subjects two times per day atbreakfast and after lunch each day for three days:

Concentration of DBHB + DBHV in a compositing containing DBHB + DBHV andComposition # D-1,3BD 1 100%  2 45% 3  0%

The panelists record gastrointestinal discomfort during each night ofthe test period. After a one-day washout period, the panelists are thenassigned to a different group during the second three day test periodand record their gastrointestinal discomfort during each night of thesecond test period. After a one-day washout period, the panelists arethen assigned to a different group during the third three-day testperiod and record their gastrointestinal discomfort during each night ofthe third test period. The results are then compared both between thesame panelists during each test period as well as an average of allpanelists for each composition. The comparisons show that ingestion ofcomposition 2 produces less gastrointestinal discomfort thancompositions 1 and 2.

Example 10: Improvements in Tolerability

The following compositions are made into a consumable beverage andingested by a panel of human test subjects:

Concentration of DBHB + DBHV in a compositing containing DBHB + DBHV andComposition # D-1,3BD 1 100%  2 45% 3  0%

Panelists are asked to consume as much of the consumable beverages astolerable up to a maximum dosage of 150 grams of the compositions perday for as many consecutive days as they can tolerate. The panelistsrecord the amounts of the consumable beverages consumed each day and thenumber of consecutive days the consumable beverages are consumed. Aftera one-week washout period, the panelists are then switched to adifferent composition # and asked to repeat the procedure for a secondperiod. After a one-week washout period, the panelists are then switchedto a different composition # and asked to repeat the procedure for athird period. The comparisons show that panelists tolerate ingestion ofcomposition 2 for significantly longer than compositions 1 and 2 and areable to tolerate ingestion of at least 100 g per day of composition 2whereas panelists are unable to tolerate ingestion of 100 g per day ofcompositions 1 and 3.

Example 11: Taste and Tolerability Comparison

The following compositions were made and tested by a panel of 10 blindedtaste testers for tolerability and taste according to the followingscales

-   -   1. The quality of the flavor of the product on a scale of 1 to        5? (1-terrible, 2-bad, 3-tolerable, 4-good, 5-excellent)    -   2. Ability to finish the entire 8 oz beverage (1-could not        finish, 2-finished with difficulty, 3-finished reluctantly,        4-easily finished 5-very easily finished    -   3. Rank all the compositions by preference (1-worst, 2-fourth        best, 3-third best, 4-second best, 5-best)

All compositions were prepared as 8 ounce beverages. They all containedan equivalent amount (10 grams) of total active ingredients comprised ofdiffering blends of ketogenic agents. In addition, each compositioncontained the exact same amounts and types of inactive ingredients,including carbonated water, sweetener and natural flavoring. The naturalflavoring contained a blend of tropical and citrus fruit juices. Theratios of active ingredients were varied for each composition as shownin the following tables:

Beverage 1 of the present disclosure containing: 48% BHB acid, 2% BHVacid, 50% 1,3BD molar molar % weight mass ratio g/mol ratio g/servingBHB Acid 104.1045 48.0% 49.97 51.3% 5.1 BHV Acid 118.06 2.0% 2.36 2.4%0.2 1,3 BD 90.12 50.0% 45.06 46.3% 4.6 100.0% 97.39 100.0% 10.0

Beverage 2 of the present disclosure containing: 72% BHB acid, 3% BHVacid, 25% 1,3BD molar molar % weight mass ratio g/mol ratio g/servingBHB Acid 104.1045 72.0% 74.96 74.2% 7.4 BHV Acid 118.06 3.0% 3.54 3.5%0.4 1,3 BD 90.12 25.0% 22.53 22.3% 2.2 100.0% 101.03 100.0% 10.0

Beverage 3 of the present disclosure containing: 24% BHB acid, 1% BHVacid 75% 1,3BD molar molar % weight mass ratio g/mol ratio g/serving BHBAcid 104.1045 24.0% 24.99 26.6% 2.7 BHV Acid 118.06 1.0% 1.18 1.3% 0.11,3 BD 90.12 75.0% 67.59 72.1% 7.2 100.0% 93.76 100.0% 10.0

Comparative Beverage 1 of US20180057846 containing: 60% BHB acid, 30%BHB salts (32% sodium, 44% potassium, 24% calcium), 10% 1,3 BD molarmolar % weight mass ratio g/mol ratio g/serving BHB Acid 104.1045 60%62.46 52% 5.2 BHB sodium 127.09 12.20 10% 1.0 BHB 142.19 30% 18.77 16%1.6 potassium BHB calcium 246.27 17.73 15% 1.5 1,3 BD 90.12 10% 9.01  7%0.7 100%  120.18 100%  10.0

Comparative Beverage 2 of US20180057846 containing: 90% BHB acid, 10%1,3BD molar weight mass % ratio g/mol ratio g/serving BHB Acid 104.104590.0% 93.69 91.2% 9.1 1,3 BD 90.12 10.0% 9.01 8.8% 0.9 100.0% 102.71100.0% 10.0Presentation: All compositions were presented simultaneously and at thesame refrigerated temperature. They were presented in the same type ofcup which were labeled with A, B, C, D and E:

A=Beverage 1 of present disclosure

B=Beverage 2 of present disclosure

C=Beverage 3 of present disclosure

D=Beverage 1 of US20180057846

E=Beverage 2 of US20180057846

Method: Participants were seated separately from each other andinstructed to not communicate amongst themselves. Their stations had acup of drinking water, a questionnaire and a pen/pencil.

The taste test coordinator presented each participant with all 5compositions (in the manner described above) and monitored theparticipants to ensure the procedure was followed properly.

The participants cleansed their palate with water, tasted product A andrecorded their answers in the ‘Product A Questionnaire’. They repeatedthis process with products B-E. Then, participants answered the finaloverall questions in the ‘Overall Experience Questionnaire’.Questionnaire responses were anonymous.

Table of comparative taste and tolerability results. Values are averageof 10 participants Ability to finish Total Quality of flavor beveragePreference ranking average Sample Average Std Dev Average Std DevAverage Std Dev score Beverage 1 of 4.8 0.40 5.0 0.00 4.9 0.30 15.1present disclosure Beverage 2 of 3.7 0.46 3.6 0.49 3.0 0.63 11.2 presentdisclosure Beverage 3 of 4.2 0.40 4.1 0.54 4.0 0.45 13.2 presentdisclosure Beverage 1 of 1.9 0.70 2.3 0.90 1.3 0.46 7.1 US20180057846Beverage 2 of 2.1 0.54 2.6 0.92 1.7 0.46 7.9 US20180057846

Example 12: Taste and Tolerability Comparison

The following compositions are made and tested by a panel of 10 blindedtaste testers for tolerability and taste according to the followingscales

-   -   1. the quality of the flavor of the product on a scale of 1 to        5? (1-terrible, 2-bad, 3-tolerable, 4-good, 5-excellent)    -   2. Ability to finish the entire 8 oz beverage (1-could not        finish, 2-finished with difficulty, 3-finished reluctantly,        4-easily finished 5-very easily finished    -   3. Rank all the compositions by preference (1-worst, 2-fourth        best, 3-third best, 4-second best, 5-best)

All compositions are prepared as 8 ounce beverages. They all contain anequivalent amount (10 grams) of total active ingredients comprised of adiffering blends of ketogenic agents. In addition, each compositioncontains the exact same amounts and types of inactive ingredients,including carbonated water, sweetener and natural flavoring. The naturalflavoring contains a blend of tropical and citrus fruits. The ratios ofactive ingredients are varied for each composition as shown in thefollowing tables:

Beverage 4 of the present disclosure containing: 50% BHB acid, 50% 1,3BDmolar molar % weight mass ratio g/mol ratio g/serving BHB Acid 104.104550.0% 52.05 53.6% 5.4 1,3 BD 90.12 50.0% 45.06 46.4% 4.6 100.0% 97.11100.0% 10.0

Comparative Beverage 2 of US20180057846 containing: 90% BHB acid, 10%1,3BD molar weight mass % ratio g/mol ratio g/serving BHB Acid 104.104590.0% 93.69 91.2% 9.1 1,3 BD 90.12 10.0% 9.01 8.8% 0.9 100.0% 102.71100.0% 10.0Presentation: All compositions were presented simultaneously and at thesame refrigerated temperature. They were presented in the same type ofcup and were labeled with A and B.

A=Beverage 4 of present disclosure

B=Comparative Beverage 2 of US20180057846

Method: Participants were seated separately from each other andinstructed to not communicate amongst themselves. Their stations had acup of drinking water, a questionnaire and a pen/pencil.

The taste test coordinator presented each participant with all 5compositions (in the manner described above) and monitored theparticipants to ensure the procedure was followed properly.

The participants cleansed their palate with water, tasted product A andrecorded their answers in the ‘Product A Questionnaire’. They repeatedthis process with product B. Then, participants answered the finaloverall questions in the ‘Overall Experience Questionnaire’.Questionnaire responses were anonymous.

Table of comparative taste parameters. Values are average of 10participants Ability to finish Total Quality of flavor beveragePreference rankkng average Sample Average Std Dev Average Std DevAverage Std Dev score Beverage 4 of 4.8 0.6 5.0 0.0 5.0 0.0 15.4 presentdisclosure Beverage 2 of 2.5 0.5 2.0 0.6 1.0 0.0 6.6 US20180057846

Those skilled in the field will understand based on the presentdisclosure that the various examples above may be scaled and altered toachieve desired results to serve specific purposes. For example, therecipes above may be scaled up for commercial purposes and adjustmentsmay be made to accommodate production on large scale equipment such asadjustments to time, temperature, and amounts of materials withoutdeparting from the scope and spirit of the present disclosure.

While the subject matter of this disclosure has been described and shownin considerable detail with reference to certain illustrativeembodiments, including various combinations and sub-combinations offeatures, those skilled in the art will readily appreciate otherembodiments and variations and modifications thereof as encompassedwithin the scope of the present disclosure. Moreover, the descriptionsof such embodiments, combinations, and sub-combinations is not intendedto convey that the claimed subject matter requires features orcombinations of features other than those expressly recited in theclaims. Accordingly, the scope of this disclosure is intended to includeall modifications and variations encompassed within the spirit and scopeof the following appended claims.

1. A beverage or food product comprising, per serving, 3 to 7 grams of(D)-β-hydroxybutyric acid and 0.5 to 8 grams of (D)-1,3 butanediol and100 to 250 grams of a consumable carrier.
 2. The beverage or foodproduct of claim 1, wherein the consumable carrier comprises water orcarbonated water, a flavoring agent, and a sweetener.
 3. The beverage orfood product of claim 2, wherein the sweetener is a sugar alcohol,stevia, allulose, monk fruit, or a combination thereof.
 4. The beverageor food product of claim 1, wherein the beverage or food product is freeof salts of (D)-β-hydroxybutyric acid.
 5. The beverage or food productof claim 1, wherein the beverage or food product is free of esters of(D)-β-hydroxybutyric acid, (D)-β-hydroxyvaleric acid, and (D)-1,3butanediol.
 6. The beverage or food product of claim 1, furthercomprising (D)-β-hydroxyvaleric acid.
 7. The beverage or food product ofclaim 1, comprising (D)-β-hydroxybutyric acid, (D)-β-hydroxyvalericacid, and (D)-1,3 butanediol in a molar ratio range of 3 to 7:0.01 to1:7 to 3 or 4 to 6:0.1 to 0.8:6 to
 5. 8. The beverage or food product ofclaim 7, wherein at least 5% of the (D)-β-hydroxyvaleric acid is in theform of a magnesium salt, potassium salt, calcium salt, or combinationthereof.
 9. The beverage or food product of claim 1, wherein thebeverage or food is in the form of a protein bar, a sports beverage,gummies, or an energy gel.
 10. The beverage or food product of claim 1,wherein the beverage or food comprises: a) 25% to 85% by weight of(D)-β-hydroxybutyric acid; b) 15% to 75% by weight (D)-1,3 butanediol,wherein the flavor of the composition is improved over an equivalentweight of either (D)-β-hydroxybutyrate or (D)-1,3 butanediol alone andover salts and esters thereof.
 11. The beverage or food product of claim10, wherein a) is 55% to 45% and b) is 45 to 55% of the composition byweight.
 12. The beverage or food product of claim 10, wherein a) is 65%to 35% and b) is 35 to 65% of the composition by weight.
 13. Thebeverage or food product of claim 10, wherein a) is 70% to 30% and b) is30 to 70% of the composition by weight.
 14. The beverage or food productof claim 10, wherein a) and b) are in a molar ratio of 7:3 to 3:7 or 4:6to 6:4.
 15. A method of making the beverage or food product of claim 1,comprising mixing 3 to 7 grams of (D)-β-hydroxybutyric acid with 0.5 to8 grams of (D)-1,3 butanediol and 100 to 250 grams of a consumablecarrier.
 16. The method of claim 15, wherein the beverage or foodproduct comprises a mixture of the (D)-β-hydroxybutyric acid and (D)-1,3butanediol in a molar ratio of 1:8 to 11 to water or carbonated water.17. The method of claim 15, wherein the beverage or food productcomprises a mixture of the (D)-β-hydroxybutyric acid and (D)-1,3butanediol in a molar ratio of 1:0.05 to 0.12 to a flavoring agent. 18.The method of claim 15, wherein the beverage or food product comprises amixture of the (D)-β-hydroxybutyric acid and (D)-1,3 butanediol in amolar ratio of 1:0.6 to 1.2 to a sweetener selected from a sugaralcohol, stevia, allulose, monk fruit, or a combination thereof.
 19. Amethod for increasing ketotic efficiency in a human body comprising:administering the beverage or food of claim 1, wherein the ketoticefficiency according to formula I Σ_(t=0) ^(n)(mMol/L)/(g/kg)*t [FormulaI] in the human subject is at least 40% higher than the administrationof an equivalent weight of either (D)-β-hydroxybutyrate or (D)-1,3butanediol alone at one hour after administration.
 20. A method ofelevating circulating ketone levels by at least 1.4 mM in a humansubject within 2 hours of administration comprising administering thefood or beverage of claim 1 to the human subject in a serving thatcomprises at least 10 grams of (D)-β-hydroxybutyric acid and (D)-1,3butanediol in a molar ratio of 7:3 to 3:7.